Recent efforts have been devoted to the conjugation of cytotoxic agents or neoplastic drugs to specific antibodies, such as monoclonal antibodies, to produce targeting protein conjugates that can selectively kill target cells (e.g., tumor cells) while sparing normal tissues. A large number of different cytotoxic agents (including beta- and alpha-emitting isotopes, plant and bacterial toxins) and a variety of drugs (including antibiotics, antiviral agents, intercalating agents, antimalarial agents, antimetabolites, antineoplastic agents, antifungal agents, and alkylating agents) have been contemplated for this purpose.
Conjugation of chemotherapeutic drugs to antibodies is undertaken for the following reasons:
1. It has recently been shown that up to a 1,000-fold increase in the amount of drug delivered to tumor cells can be attained when the drug is conjugated to an antigen-specific monoclonal antibody over the amount of delivered drug attained by the addition of free drug. PA1 2. Pleiotropic drug resistance may arise following treatment with one of a number of chemotherapeutic drugs, resulting in the inducement of resistance to drugs of several classes. The mechanism(s) of pleiotropic drug resistance are not entirely understood, but it is known that this resistance can be partially overcome by antibody targeting of drugs. PA1 3. Even though current chemotherapeutic drugs are active against only some of the major tumor types, the chemotherapeutic response rate in drug-insensitive tumor types may be increased by antibody-mediated delivery. PA1 4. Many dose limiting toxicities, which are now seen with chemotherapeutic drugs, can be decreased by conjugation to an antibody. A decrease in toxicity with at least equal efficacy would give a superior product, and such a product would have a higher therapeutic index.
Many chemotherapeutic drugs have been conjugated to monoclonal antibodies using a variety of covalent bonds (see, for example, Ghose et al., Meth. Enzymol. 93:280 (1983); Ram et al., Pharm. Res. 4:181 (1987)). One problem with covalent conjugation of drugs to antibodies is a concomitant loss of drug activity. It is believed that the strength of the covalent bond results in an inability to separate drug from antibody at the target site. Thus, there is a need in the art for a method for binding drugs to targeting agents that permits efficient release of the conjugated drug at the target site.